Human adipose-derived stem cells (ASCs) secrete cytokines and growth factors that can be harnessed in a paracrine fashion for promotion of angiogenesis, cell survival and activation of endogenous stem cells. We recently showed that hypoxia is a powerful stimulus for angiogenic activity from ASCs in vitro and here we investigate the biological significance of this paracrine activity in an in vivo angiogenesis model. A single in vitro exposure of ASCs to severe hypoxia (<0.1% O2) significantly increased both the transcriptional and translational level of VEGF-A and angiogenin (ANG). The angiogenicity of ASC conditioned media (ASCCM) was assessed by implanting ASCCM-treated polyvinyl alcohol sponges subcutaneously for 2 weeks in mice. Morphometric analysis of anti-CD31-immunolabelled sponge sections demonstrated increased angiogenesis with hypoxic ASCCM treatment compared to normoxic control ASCCM treatment (percentage vascular volume; 6.0 ± 0.5% in hypoxic ASCCM vs. 4.1 ± 0.7% in normoxic ASCCM, p < 0.05). Reduction of VEGF-A and ANG levels in ASCCM with respective neutralising antibodies before sponge implantation showed significantly diminished angiogenic response (3.5 ± 0.5% in anti-VEGF-A-treated, 3.2 ± 0.7% in anti-ANG-treated and 3.5 ± 0.6% in anti-VEGF-A/ANG-treated). Furthermore, both normoxic and hypoxic ASCCM were able to sustain in vivo lymphangiogenesis in sponges. Collectively, the model demonstrated that the increased paracrine production of VEGF-A and ANG in hypoxic-conditioned ASCs in vitro translated to an in vivo effect with favourable biological significance. These results further illustrate the potential for utilisation of in vitro optimised ASCCM for in vivo angiogenesis-related applications as an effective cell-free technology.